CN108586452A - A kind of synthetic method of Pa Boxini intermediates - Google Patents

A kind of synthetic method of Pa Boxini intermediates Download PDF

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Publication number
CN108586452A
CN108586452A CN201810030281.3A CN201810030281A CN108586452A CN 108586452 A CN108586452 A CN 108586452A CN 201810030281 A CN201810030281 A CN 201810030281A CN 108586452 A CN108586452 A CN 108586452A
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added
synthetic method
boxini
react
boxini intermediates
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潘敬坤
江信渝
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Chongqing Beisheng Pharmaceutical Technology Co Ltd
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Chongqing Beisheng Pharmaceutical Technology Co Ltd
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D471/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04Ortho-condensed systems
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D213/00Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72Nitrogen atoms
    • C07D213/73Unsubstituted amino or imino radicals

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pyridine Compounds (AREA)

Abstract

The invention discloses a kind of synthetic methods of Pa Boxini intermediates.A kind of synthetic method of Pa Boxini intermediates includes that 5 bromine, 2 nitropyridine is added in a kettle, then N Boc piperazines, alkali is added in organic solvent, and then heating is stirred to react, and react and has been added that elutriation is brilliant, and then cool down crystallization, has filtered, filter cake is washed with water;Above-mentioned solid is added in organic solvent, is dissolved by heating to clarifying, then cooling crystallization, filtering is dried under reduced pressure;Desciccate is added in autoclave, methanol, reducing agent is then added, temperature reaction is stirred to react after the completion of reaction, is filtered, and filter cake is washed with methanol, collects filtrate, reduced pressure, extraction, distillation, crystallization, filtering are to get product.The present invention is artificial chemical synthesis Pa Boxini intermediates, provides a kind of cheap industrialized producing technology for Pa Boxini intermediates, process route is easy to operate, and reaction condition is mild, reaction process is safe and environment-friendly, raw material is cheap and easy to get, and industrial Applicability is strong.

Description

A kind of synthetic method of Pa Boxini intermediates
Technical field
The present invention relates to field of medicaments, and in particular to a kind of synthetic method of Pa Boxini intermediates.
Background technology
On 2 3rd, 2015 FDA acceleration have approved Pfizer listing Pa Boxini (Palbociclib, ) gamma therapy of the joint Letrozole as endocrine basis, treat the advanced breast cancer of menopausal woman estrogen receptor 2 feminine gender Patient.It is each to be used to treat ER+/HER2- postmenopausal women with advanced breast cancer.Pa Boxini can make breast cancer get nowhere life compared with Letrozole One times of phase extension is deposited, is the new hope of patient with breast cancer, curative effect is broken through, and can replace the clinical application of Letrozole completely. Pa Boxini is the first CDK4/6 kinase inhibitors listing in the whole world.
The main synthetic methods of Pa Boxini are 4- (6- aminopyridine -3- bases) piperazine-carboxylic acid tert-butyl esters and the bromo- 2- of 6- Simultaneously [2,3-D] pyrimidine -7 (8H) -one is condensed chloro- 8- cyclopenta -5- methvl-pyridiniums, is then reacted through heck, then through remove-insurance Shield, both at salt.
The synthesis of wherein 4- (6- aminopyridine -3- bases) piperazine-carboxylic acid tert-butyl ester mainly has following according to the literature Two synthesis routes:
It is described, is condensed in the tert-butyl alcohol with piperazine using the chloro- 2- nitropyridines of 5-, then according to WO2010020675 techniques In tetrahydrofuran, using potassium carbonate as alkali, with the amino that Boc protections are free, then restore to obtain product through Raney's nickel.It uses When this method prepares condensation product, with the presence of a large amount of dimer, and it is more difficult refined.Then it is restored using Raney's nickel, there are larger Security risk.
According to document US20160002223, using the bromo- 2- nitropyridines of 5- and N-Boc piperazines, anhydrous lithium chloride with And under the action of triethylamine, through condensation, is then restored through palladium carbon, obtain finished product.Using the palladium carbon of high price as reducing agent, cost It is higher, and the color of product is poor.
Invention content
That the object of the present invention is to provide a kind of process routes is simple, reaction condition is mild, production cost is low, process safety ring It protects, the synthetic method for the Pa Boxini intermediates that raw material is cheap and easy to get, industrial Applicability is strong.
The present invention is achieved by the following technical solution:
A kind of synthetic method of Pa Boxini intermediates includes step:
S1. the bromo- 2- nitropyridines of 5- are added in a kettle, then N-Boc- piperazines, alkali is added, then in organic solvent Heating is stirred to react, and reaction is completed to be slowly added to elutriation crystalline substance, and stirring and crystallizing, then cool down crystallization, and filtering, filter cake is washed with water;
S2. above-mentioned solid is added in organic solvent, is dissolved by heating to clarifying, then cooling crystallization, filtering, decompression are dry It is dry to obtain 1-Boc-4- (6- nitro -3- pyridines) piperazine;
S3. 1-Boc-4- (6- nitro -3- pyridines) piperazine is added in autoclave, methanol, reducing agent, heating is then added Reaction is stirred to react 12h after the completion of reaction, filters, and filter cake washs with methanol, collects filtrate, 40 DEG C be concentrated under reduced pressure into it is thick, Extracted, distillation, crystallization, filtering are to get product.
Further, in the synthetic method of above-mentioned Pa Boxini intermediates, what the heating in the step S1 was stirred to react Reaction temperature is 50-80 DEG C, reaction time 10-20h.
It is further preferred that in the synthetic method of above-mentioned Pa Boxini intermediates, the heating stirring in the step S1 is anti- The reaction temperature answered is 60-65 DEG C, reaction time 17h.
Further, in the synthetic method of above-mentioned Pa Boxini intermediates, the organic solvent in the step S1 is diformazan One or more of base sulfoxide, N,N-dimethylformamide, acetonitrile, the tert-butyl alcohol, methanol, ethyl alcohol mix.
Further, in the synthetic method of above-mentioned Pa Boxini intermediates, alkali in the step S1 is triethylamine, two different In propylethylamine, potassium carbonate, sodium carbonate, sodium bicarbonate, saleratus, sodium hydroxide, potassium hydroxide, sodium acetate, potassium phosphate One or more mixing.
Further, in the synthetic method of above-mentioned Pa Boxini intermediates, the dosage of the alkali in the step S1 is 1.0- 1.5eq, i.e. 1mol N-Boc- piperazines use the alkali of 1.0-1.5mol, and the dosage of further preferred alkali is 1.2eq.
Further, in the synthetic method of above-mentioned Pa Boxini intermediates, appropriate organic solvent is first in the step S2 One or more of benzene, ethyl acetate, isopropyl acetate, methanol, ethyl alcohol, acetonitrile mix.
Further, in the synthetic method of above-mentioned Pa Boxini intermediates, the reducing agent in the step S3 is iron powder, thunder One or more of Buddhist nun's nickel, Metal Palladium reducing agent, vulcanized sodium, sulfuric acid sodium hydrate mix.
Further, in the synthetic method of above-mentioned Pa Boxini intermediates, the extraction step in the step S3 is extraction, Used extractant is the mixing of one or more of ethyl acetate, dichloromethane, toluene, isopropyl acetate;The step Solvent used in Devitrification step in rapid S3 be methyl tertiary butyl ether, toluene, normal heptane, petroleum ether, one kind in n-hexane or Several mixing.
Further, in the synthetic method of above-mentioned Pa Boxini intermediates, bromo- 2- nitropyridines of 5- in the step S1, N-Boc- piperazines, alkali quality amount ratio be 10:(10-12);1-Boc-4- (6- nitro -3- pyridines) piperazine in the step S3 Quality amount ratio with reducing agent is 10:(12-16).
The present invention is artificial chemical synthesis Pa Boxini intermediates, and a kind of cheap work is provided for Pa Boxini intermediates Industry metaplasia production. art, process route is easy to operate, and reaction condition is mild, reaction process is safe and environment-friendly, raw material is cheap and easy to get, work Industry is adaptable.
Specific implementation mode
With reference to specific embodiment, the present invention will be further described.The embodiment is only the preferred implementation of the present invention Example, is not intended to restrict the invention, for those skilled in the art, the present invention can have various changes and change Change.All within the spirits and principles of the present invention, any modification, equivalent replacement, improvement and so on should be included in the present invention Protection domain within.In each embodiment parts by weight are referred both to without signified component number in the case of specified otherwise.
Embodiment 1
In 250mL flasks, the bromo- 2- nitropyridines of 10g5- are added, 25mLDMSO is added, N-Boc- piperazines are then added Then triethylamine 7.5g is added in 11.96g, then heating up 60 DEG C is stirred to react 17 hours.60 DEG C of temperature control, is slowly added to 25g water, It is stirred to react 1 hour, is then cooled to 20-25 DEG C, be stirred to react 1 hour, filter, filter cake is washed with 6 × 50mL of water to PH= 7, it dries in air.
Above-mentioned solid is added in 100mL ethyl alcohol, is heated to flowing back, orange solution is obtained, is subsequently cooled to 20-25 DEG C, it stirs 1 hour, filtering, filter cake is washed with ethyl alcohol 10mL, is dried under reduced pressure in 55 DEG C 7 hours, obtains 1-Boc-4- (6- nitros- 3- pyridines) piperazine, it is 99.4% that the molar yield of 1-Boc-4- (6- nitro -3- pyridines) piperazine, which is 89.5%, HPLC purity,.
10g1-Boc-4- (6- nitro -3- pyridines) piperazine is added in 500mL reaction kettles, 100mL methanol is then added, Then nine water vulcanized sodium of 15.14g is added.It is warming up to 35-40 DEG C, is stirred to react 12 hours, is filtered, filter cake is washed with 10mL methanol It washs, collects filtrate, thick, addition 50g dichloromethane, water 25g, liquid separation, collected organic layer, in 40 are concentrated under reduced pressure at 40 DEG C It DEG C is concentrated to dryness, then methyl tertiary butyl ether(MTBE) 20g is beaten, and under conditions of 20-25 DEG C, is stirred 1 hour, is cooled to 0-5 DEG C, it stirs 1 hour, filtering, filter cake is washed with methyl tertiary butyl ether(MTBE) 10mL, 12 hours dry at 50 DEG C, is obtained yellow solid, is produced Product molar yield is that 86%, HPLC purity is 99.6%.
Embodiment 2
In 250mL flasks, the bromo- 2- nitropyridines of 10g5- are added, the 25mL tert-butyl alcohols are added, N-Boc- piperazines are then added Then potassium carbonate 7.5g is added in piperazine 11.96g, then heating up 60 DEG C is stirred to react 17 hours.60 DEG C of temperature control, is slowly added to 25g Water is stirred to react 1 hour, is then cooled to 20-25 DEG C, is stirred to react 1 hour, and filtering, filter cake is washed with 6 × 50mL of water to PH =7, it dries in air.
Above-mentioned solid is added in 100mL ethyl alcohol, is heated to flowing back, orange solution is obtained, is subsequently cooled to 20-25 DEG C, it stirs 1 hour, filtering, filter cake is washed with ethyl alcohol 10mL, is dried under reduced pressure in 55 DEG C 7 hours, obtains 1-Boc-4- (6- nitros- 3- pyridines) piperazine, it is 99.3% that the molar yield of 1-Boc-4- (6- nitro -3- pyridines) piperazine, which is 88.9%, HPLC purity,.
10g1-Boc-4- (6- nitro -3- pyridines) piperazine is added in 500mL reaction kettles, 100mL methanol is then added, Then 15g iron powders are added.It is warming up to 35-40 DEG C, is stirred to react 12 hours, is filtered, filter cake is washed with 10mL methanol, collects filter Liquid, is concentrated under reduced pressure at 40 DEG C thick, is added 50g dichloromethane, water 25g, liquid separation, and collected organic layer is dense in 40 DEG C of decompressions It is reduced to dry, then methyl tertiary butyl ether(MTBE) 20g mashing, under conditions of 20-25 DEG C, stirring 1 hour is cooled to 0-5 DEG C, stirring 1 Hour, filtering, filter cake is washed with methyl tertiary butyl ether(MTBE) 10mL, 12 hours dry at 50 DEG C, obtains yellow solid, and molar product is received Rate is that 88%, HPLC purity is 99.6%.
Embodiment 3
In 250mL flasks, the bromo- 2- nitropyridines of 10g5- are added, 25mL n,N-Dimethylformamide is added, then add Enter N-Boc- piperazine 11.96g, diisopropylethylamine 7.9g is then added, then heating up 60 DEG C is stirred to react 17 hours.Temperature control 60 DEG C, it is slowly added to 25g water, is stirred to react 1 hour, is then cooled to 20-25 DEG C, is stirred to react 1 hour, is filtered, filter cake water 6 × 50mL is washed to PH=7, is dried in air.
Above-mentioned solid is added in 100mL ethyl alcohol, is heated to flowing back, orange solution is obtained, is subsequently cooled to 20-25 DEG C, it stirs 1 hour, filtering, filter cake is washed with ethyl alcohol 10mL, is dried under reduced pressure in 55 DEG C 7 hours, obtains 1-Boc-4- (6- nitros- 3- pyridines) piperazine, it is 99.3% that the molar yield of 1-Boc-4- (6- nitro -3- pyridines) piperazine, which is 90.2%, HPLC purity,.
10g1-Boc-4- (6- nitro -3- pyridines) piperazine is added in 500mL reaction kettles, 100mL methanol is then added, Then 14.23g Raney's nickels are added.It is warming up to 35-40 DEG C, is stirred to react 12 hours, is filtered, filter cake is washed with 10mL methanol, is received Collect filtrate, be concentrated under reduced pressure at 40 DEG C thick, be added 50g dichloromethane, water 25g, liquid separation, collected organic layer subtracts in 40 DEG C Pressure is concentrated to dryness, and then methyl tertiary butyl ether(MTBE) 20g is beaten, and under conditions of 20-25 DEG C, is stirred 1 hour, is cooled to 0-5 DEG C, stirs It mixes 1 hour, filters, filter cake is washed with methyl tertiary butyl ether(MTBE) 10mL, 12 hours dry at 50 DEG C, obtains yellow solid, product rubs It is 99.5% that your yield, which is 87%, HPLC purity,.

Claims (10)

1. a kind of synthetic method of Pa Boxini intermediates, which is characterized in that including step:
S1. the bromo- 2- nitropyridines of 5- are added in a kettle, then organic solvent is added N-Boc- piperazines, alkali, then heats up It is stirred to react, reaction is completed to be slowly added to elutriation crystalline substance, and stirring and crystallizing, then cool down crystallization, and filtering, filter cake is washed with water;
S2. above-mentioned solid is added in organic solvent, is dissolved by heating to clarifying, then cooling crystallization, filtering is dried under reduced pressure 1-Boc-4- (6- nitro -3- pyridines) piperazine;
S3. 1-Boc-4- (6- nitro -3- pyridines) piperazine is added in autoclave, methanol, reducing agent is then added, heating is anti- It answers, 12h is stirred to react after the completion of reaction, filter, filter cake is washed with methanol, collects filtrate, and 40 DEG C are concentrated under reduced pressure into thick, warp Extraction, distillation, crystallization, filtering are to get product.
2. the synthetic method of Pa Boxini intermediates according to claim 1, which is characterized in that
The reaction temperature that heating in the step S1 is stirred to react is 50-80 DEG C, reaction time 10-20h.
3. the synthetic method of Pa Boxini intermediates according to claim 1, which is characterized in that
The reaction temperature that heating in the step S1 is stirred to react is 60-65 DEG C, reaction time 17h.
4. the synthetic method of Pa Boxini intermediates according to claim 1, which is characterized in that
Organic solvent in the step S1 is dimethyl sulfoxide (DMSO), N,N-dimethylformamide, acetonitrile, the tert-butyl alcohol, methanol, ethyl alcohol One or more of mixing.
5. the synthetic method of Pa Boxini intermediates according to claim 1, which is characterized in that
Alkali in the step S1 is triethylamine, diisopropylethylamine, potassium carbonate, sodium carbonate, sodium bicarbonate, saleratus, hydrogen One or more of sodium oxide molybdena, potassium hydroxide, sodium acetate, potassium phosphate mix.
6. the synthetic method of Pa Boxini intermediates according to claim 5, which is characterized in that
The dosage of alkali in the step S1 is 1.0-1.5eq.
7. the synthetic method of Pa Boxini intermediates according to claim 1, which is characterized in that
Appropriate organic solvent is one kind in toluene, ethyl acetate, isopropyl acetate, methanol, ethyl alcohol, acetonitrile in the step S2 Or several mixing.
8. the synthetic method of Pa Boxini intermediates according to claim 1, which is characterized in that
Reducing agent in the step S3 is one in iron powder, Raney's nickel, Metal Palladium reducing agent, vulcanized sodium, sulfuric acid sodium hydrate Kind or several mixing.
9. the synthetic method of Pa Boxini intermediates according to claim 1, which is characterized in that
Extraction step in the step S3 is extraction, and used extractant is ethyl acetate, dichloromethane, toluene, vinegar One or more of isopropyl propionate mixes;
Solvent used in Devitrification step in the step S3 is methyl tertiary butyl ether, toluene, normal heptane, petroleum ether, n-hexane One or more of mixing.
10. the synthetic method of Pa Boxini intermediates as claimed in any of claims 1 to 9, which is characterized in that
Bromo- 2- nitropyridines of 5- in the step S1, N-Boc- piperazines, alkali quality amount ratio be 10:(10-12);
The quality amount ratio of 1-Boc-4- (6- nitro -3- pyridines) piperazines and reducing agent is 10 in the step S3:(12-16).
CN201810030281.3A 2018-01-12 2018-01-12 A kind of synthetic method of Pa Boxini intermediates Pending CN108586452A (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109320511A (en) * 2018-10-26 2019-02-12 广安凯特制药有限公司 A kind of high-purity Pa Boxini intermediate product and preparation method thereof
CN112724078A (en) * 2021-01-13 2021-04-30 山东邹平大展新材料有限公司 Method for removing impurities of piparide intermediate

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101001857A (en) * 2002-01-22 2007-07-18 沃尼尔·朗伯有限责任公司 2-(pyridin-2-ylamino)-pyrido [2,3-d]pyrimidin-7-ones
CN101163694A (en) * 2005-03-08 2008-04-16 阿斯利康(瑞典)有限公司 Imidaz0l0-5-yl-2-anil0-pyrimidines as agents for the inhibition of cell proliferation
CN101511829A (en) * 2006-09-08 2009-08-19 辉瑞产品公司 Synthesis of 2-(pyridin-2-ylamino)-pyrido[2,3-d]pyrimidin-7-ones
CN102369187A (en) * 2009-03-02 2012-03-07 Irm责任有限公司 N- (hetero)aryl, 2- (hetero)aryl-substituted acetamides for use as wnt signaling modulators
CN105008357A (en) * 2013-02-21 2015-10-28 辉瑞大药厂 Solid forms of a selective CDK4/6 inhibitor

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101001857A (en) * 2002-01-22 2007-07-18 沃尼尔·朗伯有限责任公司 2-(pyridin-2-ylamino)-pyrido [2,3-d]pyrimidin-7-ones
CN101163694A (en) * 2005-03-08 2008-04-16 阿斯利康(瑞典)有限公司 Imidaz0l0-5-yl-2-anil0-pyrimidines as agents for the inhibition of cell proliferation
CN101511829A (en) * 2006-09-08 2009-08-19 辉瑞产品公司 Synthesis of 2-(pyridin-2-ylamino)-pyrido[2,3-d]pyrimidin-7-ones
CN102369187A (en) * 2009-03-02 2012-03-07 Irm责任有限公司 N- (hetero)aryl, 2- (hetero)aryl-substituted acetamides for use as wnt signaling modulators
CN105008357A (en) * 2013-02-21 2015-10-28 辉瑞大药厂 Solid forms of a selective CDK4/6 inhibitor

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109320511A (en) * 2018-10-26 2019-02-12 广安凯特制药有限公司 A kind of high-purity Pa Boxini intermediate product and preparation method thereof
CN112724078A (en) * 2021-01-13 2021-04-30 山东邹平大展新材料有限公司 Method for removing impurities of piparide intermediate

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Application publication date: 20180928